Project Abstract: Obesity is associated with over 630,000 (40%) of all new cases of malignant neoplasms diagnosed annually in the United States1, and a high body mass index (BMI) increases the risk of over seventeen types of solid tumors2. Mounting evidence suggests that in addition to promoting cell proliferation, obesity may also drive the development of cancer by creating a state of chronic inflammation. Moreover, adiposity and high fat diet (HFD) has been shown to promote reactive oxidative stress (ROS) and impede normal immune function. Recent pan-cancer analyses have identified somatic mutation signatures associated with specific etiologies that promote cancer, such as cigarette smoke, UV radiation, defects in DNA repair, aging and possibly, inflammation. The genomic and functional impact of obesity, and its connection to inflammation, have not been well-elucidated in humans due to complex genetic and environmental heterogeneity. Previous work by our lab and others has identified carcinogen and ROS-related mutation signatures in mouse models of human cancers. In addition, using an interspecific backcross mouse model of skin cancer, we identified quantitative-trait loci (QTL) linked to high BMI, increased papilloma burden and progression to carcinomas. A significant female-specific QTL was centered on the leptin receptor gene (LEPR), whose expression is strongly correlated with genes enriched for cytokine signaling and immune response. Here, using established models of genetic and dietary obesity in mice, I will investigate possible mechanisms by which obesity or HFD can promote cancer. First, I will test the hypothesis that obesity mediates a chronic inflammatory response that promotes cancer by creating patterns of somatic mutation signatures consistent with excess ROS production, advanced cellular aging, or impaired DNA repair by determining with whole-genome sequencing if there is evidence of an obesity-associated genomic tumor mutation signature. Next I will test the hypothesis that obesity promotes upregulation of adipokine signaling pathways in tumors and stromal cells and induces transcriptomic signatures of inflammation in tumor-infiltrating immune cells. Finally, I will evaluate if dietary obesity affects the proliferation or development of cancer stem cells by performing lineage tracing using an inducible-Cre reporter mouse expressing LGR6, a stem cell marker of carcinomas in epithelial tissues. Together, using state-of-the-art multi-omic, computational and molecular tools, these aims will evaluate the role of the obesity-inflammation axis in promoting cancer and identify candidate genetic, functional and developmental targets for downstream mechanistic studies and therapeutic avenues.